title: Heat shock instructs hESCs to exit from the self-renewal program through negative regulation of OCT4 by SAPK/JNK and HSF1 pathway.
abstract: Environmental factors affect self-renewal of stem cells by modulating the components of self-renewal networks. Heat shock, an environmental factor, induces heat shock factors (HSFs), which up-regulate stress response-related genes. However, the link of heat shock to self-renewal of stem cells has not been elucidated yet. Here, we present the direct link of heat shock to a core stem cell regulator, OCT4, in the self-renewal network through SAPK/JNK and HSF1 pathway. We first showed that heat shock initiated differentiation of human embryonic stem cells (hESCs). Gene expression analysis revealed that heat shock increased the expression of many genes involved in cellular processes related to differentiation of stem cells. We then examined the effects of HSFs induced by heat shock on core self-renewal factors. Among HSFs, heat shock induced mainly HSF1 in hESCs. The HSF1 repressed the expression of OCT4, leading to the differentiation of hESCs and the above differentiation-related gene expression change. We further examined the effects of the upstream MAP (mitogen-activated protein) kinases of HSF1 on the repression of OCT4 expression by HSF1. Among the MAP kinases, SAPK/JNK controlled predominantly the repression of the OCT4 expression by HSF1. The direct link of heat shock to the core self-renewal regulator through SAPK/JNK and HSF1 provides a fundamental basis for understanding the effect of heat and other stresses involving activation of HSF1 on the self-renewal program and further controlling differentiation of hESCs in a broad spectrum of stem cell applications using these stresses.
authors.affiliation: Center for Genomics and Proteomics & Stem Cell Core Facility, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Republic of Korea; Department of Anatomy and Cell Biology, Gachon University Medical School, Incheon 406-840, Republic of Korea.
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Byun
authors.forename: Taek-Kyun
authors.initials: TK
authors.lastname: Kim
authors.forename: Jeehyun
authors.initials: J
authors.lastname: Oh
authors.forename: Enkhjargal
authors.initials: E
authors.lastname: Bayarsaikhan
authors.forename: Daesik
authors.initials: D
authors.lastname: Kim
authors.forename: Min Young
authors.initials: MY
authors.lastname: Lee
authors.forename: Chan-Gi
authors.initials: CG
authors.lastname: Pack
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.forename: Bonghee
authors.initials: B
authors.lastname: Lee
mesh_terms: D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D000076249:Heat Shock Transcription Factors; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013696:Temperature; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8
keywords: ChIP; Chromatin-Immunoprecipitation; DAVID; DEGs; DMEM; Database for Annotation, Visualization and Integrated Discovery; Dulbecco's modified Eagle's medium; EBs; GO biological processes; GOBPs; HSFs; HSPs; KOSR; MAP; MEF; NEAA; NMF; TFs; differentially expressed genes; embryoid bodies; hESCs; heat shock factors; heat shock proteins; human embryonic stem cells; knockout serum replacement; mESCS; mitogen-activated protein; mouse embryonic fibroblast feeder; mouse embryonic stem cells; non-essential amino acid; non-negative matrix factorization; siHSF1; siRNA targeting HSF1; transcription factors.